MOLECULAR BASIS OF RESISTANCE TO ANTI-PLATELET AGENTS

抗血小板药物耐药性的分子基础

• 批准号: 7615045
• 负责人: Eric Jeffrey Topol
• 金额: $ 31.28万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7615045
• 关键词: ADP Receptors; Accounting; Address; African American; Aspirin; Atherosclerosis; Biological Assay; Blood Platelets; Blood Vessels; Candidate Disease Gene; Cataloging; Catalogs; Cessation of life; Clinical; Collaborations; Coronary; Data; Doctor of Medicine; Dose; End Point; Enrollment; Event; Fostering; Future; Gene Activation; Gene Expression Profile; Genes; Genetic Heterogeneity; Genomics; Genotype; Goals; Haplotypes; Heterogeneity; Individual; Intervention; Link; Maps; Measurement; Measures; Medicine; Minority; Molecular; Mutation; Myocardial Infarction; Natural History; Numbers; Other Genetics; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Placebos; Platelet Activation; Platelet Aggregation Inhibition; Population; Prevention therapy; Principal Investigator; Procedures; Prophylactic treatment; Proteomics; Randomized; Receptor Gene; Recording of previous events; Research Personnel; Resistance; Risk; Single Nucleotide Polymorphism; Stroke; Thromboxanes; Upper arm; Variant; base; clopidogrel; cohort; day; diagnostic catheterization; gain of function mutation; monocyte; programs; response; thienopyridine; urinary

Aspirin and the thienopyridine clopidogrel have become the mainstay of anti-platelet therapy for prevention of complications of atherosclerotic vascular disease. In recent years, we and others have demonstrated that a significant minority of patients do not achieve the anticipated level of inhibition of platelet aggregation to either aspirin or clopidogrel. Despite several studies that have characterized aspirin and clopidogrel resistance in terms of their natural history and propensity for adverse clinical events, the genomic or proteomic basis for this phenomenon has not yet been defined. Based on preliminary data generated by our group and others, we hypothesize that specific genomic variations account for the marked heterogeneity in response to anti-platelet agents. The principal goal of this project will be to assess whether genotype or platelet phenotype is more predictive of response to antiplatelet therapy and clinical outcome. In Aim 1, we will utilize a haplotype map of the P2RY12 ADP receptor gene to evaluate the significance of genetic heterogeneity with respect to clinical evidence of resistance to clopidogrel in 5000 patients from the CHARISMA trial. In Aim 2, we plan to validate our observation of an association of the P2RY1 C/T893 single nucleotide polymorphism (SNP) with aspirin resistance. We will also assess other SNPs that may be linked to aspirin resistance using a candidate gene and platelet transcriptome approach. In Aim 3, using a prospectively enrolled cohort of patients (n=500) undergoing coronary intervention treated with aspirin + clopidogrel, we will determine whether the genomic abnormalities associated with aspirin and/or clopidogrel resistance identified in Aims 1 and 2 are associated with adverse peri-procedural and one year outcomes. We will further evaluate whether specific phenotypes are important in determining response to clopidogrel and aspirin therapy. At 30 days, patients with suboptimal functional aspirin or clopidogrel effect will have drug doses increased for 30 days and followed to 60 days post-procedure for serial measurement of platelet function. The significance of this project on the practice of medicine is particularly critical. More than 20 million individuals in the US take aspirin for prophylaxis of heart attack, stroke and death. Clopidogrel is prescribed yearly in >2 million patients in the US. Currently, there is no way to individually adjust the dose of anti-platelet therapy according to the genomic profile or functional platelet assay. The results of this project will illuminate the specific pathways to make dose and agent selection individualized and promote rational use of anti-platelet agents in the future.

阿司匹林和硫吡啶氯吡格雷已成为抗低位疗法的中流 预防动脉粥样硬化血管疾病的并发症。近年来，我们和其他人有 证明很少有少数患者无法达到预期的抑制水平 血小板聚集到阿司匹林或氯吡格雷。尽管有几项研究是阿司匹林的特征 以及氯吡格雷的自然病史和对不良临床事件的倾向， 该现象的基因组或蛋白质组学基础尚未定义。基于初步数据 由我们的小组和其他人产生，我们假设特定的基因组变异解释了 响应抗血小板药物的明显异质性。该项目的主要目标是 评估基因型或血小板表型是否更能预测对抗血小板疗法的反应和 临床结果。在AIM 1中，我们将利用P2RY12 ADP受体基因的单倍型图来评估 遗传异质性在抗氯吡格雷抗性的临床证据方面的重要性 来自魅力试验的5000名患者。在AIM 2中，我们计划验证我们对 具有阿司匹林耐药性的P2RY1 C/T893单核苷酸多态性（SNP）。我们还将评估 使用候选基因和血小板转录组可能与阿司匹林抗性相关的其他SNP 方法。在AIM 3中，使用前瞻性招募的患者队列（n = 500）接受冠状动脉 用阿司匹林 +氯吡格雷治疗的干预措施，我们将确定基因组异常是否 与AIMS 1和2中鉴定的阿司匹林和/或氯吡格雷抗性相关 围场和一年的结果。我们将进一步评估特定表型是否重要 在确定对氯吡格雷和阿司匹林治疗的反应时。 30天，次优的患者 功能性阿司匹林或氯吡格雷效应将增加30天的药物剂量，然后60天 血小板功能串行测量后的过程。该项目对实践的意义 医学特别关键。美国有超过2000万个人服用阿司匹林进行预防 心脏病发作，中风和死亡。在美国，氯吡格雷每年在200万患者中开处方。现在， 没有办法根据基因组特征或 功能血小板测定。该项目的结果将阐明剂量的特定途径 代理选择个性化并促进了抗血小板剂的合理使用。